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Updated: Sep 13, 2025

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Previously undescribed effects and mechanisms of STAT3 in HPV-induced DNA re-replication in response to DNA damage

Yiying Song1, Chengzhi Gui2, Qingqing Xian1

  • 1Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China.

The FEBS Journal
|July 25, 2025
PubMed

Insights

Human papillomavirus (HPV) E7 oncoprotein drives cervical cancer by causing polyploidy. This occurs through a novel STAT3-WDHD1-UHRF1 pathway, leading to DNA re-replication and genomic instability.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Virology

Background:

  • Polyploidy is a key factor in cervical carcinogenesis.
  • The mechanism of HPV E7 oncoprotein-induced cell cycle G2 phase re-replication is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which HPV E7 induces G2 phase re-replication and polyploidy.
  • To identify the regulatory pathways involved in HPV E7-mediated genomic instability.

Main Methods:

  • Investigated the role of WDHD1 in viral oncogene-induced re-replication.
  • Examined the activation of STAT3 signaling by HPV E7.
  • Analyzed the transcriptional upregulation of WDHD1 and UHRF1.
  • Studied the interaction between STAT3, WDHD1, and UHRF1.

Main Results:

  • HPV E7 activates STAT3 signaling, upregulating WDHD1 and UHRF1.
  • STAT3 directly enhances WDHD1 gene expression.
  • UHRF1 post-transcriptionally stabilizes WDHD1, creating a feedforward loop.
  • This loop drives G2-phase re-replication and polyploidy.

Conclusions:

  • A novel STAT3-WDHD1-UHRF1 regulatory axis drives HPV E7-induced polyploid genomic instability.
  • HPV E7-induced polyploidy is a STAT3-dependent process with multilayer regulatory crosstalk.
  • These findings offer potential therapeutic targets for viral oncogenesis.
Keywords:
DNA re‐replicationHPVSTAT3UHRF1WDHD1

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